The present invention relates to liquid controlled release formulations useful as delivery systems. In particular, the present invention relates to microcapsular controlled release formulations in liquid dosage forms which are prepared via a multiple emulsion process.
Controlled release formulations, especially for the administration of therapeutically active materials, are well known in the art. Solid controlled release formulations are most common. These solid controlled release formulations can be in tablet form and often comprise a core of a therapeutically active material which is coated with varying thicknesses of inactive digestible materials. Other solid controlled release formulations comprise alternating layers of therapeutically active materials and inactive digestible materials.
Controlled release formulations in liquid form are not as common in the art as solid controlled release formulations. A basic kind of liquid controlled release formulation comprises a suspension of an ion exchange resin in finely divided form complexed with a pharmaceutical, such as that disclosed in U.S. Pat. No. 2,990,332. This kind of formulation provides only a minor delay in release. Still further, these finely divided ion exchange resins are generally not available in the specific particle sizes needed to achieve a specific desired release rate. Even further, such formulations have additional disadvantages in that they have large particle sizes and thus are not suitable for injectable routes of administration. Further, they are not storage stable and/or have only a short shelf-life due to limited stability. Moreover, these suspensions must be well-mixed prior to administration. Particular problems may arise upon transfer of unmixed suspensions to another container, since a homogeneous sample would not be present in the new container and accurate dosing would now be an impossibility.
Still another disadvantage of these suspensions is that they are gritty to the taste. Many of these disadvantages tend to lower patient compliance, and irregular blood levels of the desired drug may result.
Various other liquid controlled release formulations have been suggested by the art. PCT Application WO No. 85/03000 describes as sustained release liquid dosage formulation produced by coating a pre-made solid controlled release dosage form with a dual coating and subsequently dispersing the resulting dosage forms in a liquid carrier. Disadvantages inherent with this method include the requirement for a pre-made controlled release form, thus these formulations are not prepared in situ and they require at least two further processing steps to achieve a liquid dosage form.
Another method for producing liquid controlled release formulations is disclosed in U.S. Pat. No. 4,205,060. That method involves first forming microcapsules which are recovered as a dry powder and subsequently dispersing the powder in a liquid vehicle. Again, however, the final product of this method is a dry powder, thereby requiring further processing to arrive at a liquid formulation. Further, a larger particle size, on the order of 20-30 microns, oftentimes results, thus lending a gritty texture to the final product.
An additional method is disclosed in U.S. Pat. No. 5,221,778, wherein a substantial portion of drug-resin complexes are treated with a solvating agent and are then provided with a water-permeable diffusion barrier coating. This method, however, also results in dry particles and additionally requires a separate coating step. The coating may be achieved by employing an air suspension or fluidized bed coating apparatus. Thus, the search for an improved liquid controlled release formulation is still sought by the art.